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ORIGINAL RESEARCH |
From the Laboratory of Perinatal Medicine, Perinatal Medicine Unit, Department of Obstetrics and Gynecology, Pathology, and Medical Research Center, Pontificia Universidad Católica de Chile School of Medicine, Santiago, Chile; and San Bernardino County Medical Center, San Bernardino, California.
Address reprint requests to: Alfredo M. Germain, MD Department of Obstetrics and Gynecology Pontificia Universidad Católica de Chile PO Box 114-D Santiago Chile E-mail: agermain{at}med.puc.cl
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Abstract |
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Methods: Perinatal outcomes were evaluated for 145 consecutive patients with preterm labor, subdivided into etiologic categories according to clinical, functional (Doppler), and morphologic (placental pathology) characteristics. A group of 44 normal pregnancies delivered at term served as controls.
Results: Of the preterm labor group, 28.3% were classified as ischemic, compared with 4.5% of the control group (odds ratio and 95% confidence interval = 8.28 [1.8, 51.8]; P < .05). Compared with the control group, the preterm labor patients who delivered preterm had higher rates of ischemia (31.4% compared with 4.5%; P < .05) and infection (16.1% compared with 2.3%; P < .05). Among the preterm labor group, patients classified in the infectious or ischemic subgroups had a higher rate of preterm delivery (95.0% and 90.2% compared with 73.2%; P < .05), admission to the neonatal intensive care unit (75.0% and 61.0% compared with 40.0%; P < .05), and newborn weight under 1500 g (35.0% and 19.5% compared with 3.7%; P < .05) than the idiopathic subgroup.
Conclusion: Preterm labor resulting from infection or ischemia is associated with a higher perinatal complication rate than idiopathic preterm labor.
Preterm birth accounts for 6–10% of all births and is a major cause of perinatal morbidity and mortality. In recent years, it has become increasingly clear that preterm labor should be considered a syndrome.1,2 Attempts to elucidate the cause of preterm labor have focused mainly on intrauterine infection, which accounts for approximately 13% of all premature deliveries and is responsible for most of the adverse perinatal outcome.3–6
However, the cause of most preterm births remains unexplained. Over the last 5 years, evidence supporting a relationship between uteroplacental ischemia and preterm labor has accumulated. Both clinical findings and the high incidence of decidual vascular abnormalities in placentas of preterm deliveries are consistent with this hypothesis.1,2,6,7
The purpose of this study was to correlate placental pathology findings with the clinical course of pregnancy in patients presenting in preterm labor with intact membranes. Our main objective was to assess the relevance of ischemia to the genesis of preterm delivery. We also documented the perinatal outcomes for those subgroups.
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Materials and Methods |
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We included in the study group all patients admitted with preterm (less than 37 weeks’ gestation) labor, defined as the presence of persistent uterine contractions (at least eight uterine contractions in a 1-hour period). In addition, they did not respond to bed rest and saline infusion (1000 mL) accompanied by progressive cervical dilation (or dilation greater than 2 cm) and progressive cervical effacement (or effacement greater than 80%). All patients had intact membranes.
The clinical management included admission vaginal aerobic cultures (including group B streptococci and gonococci) and specific cultures for mycoplasma/urea-plasma. Patients with positive cultures for pathogenic microorganisms were treated with appropriate antibiotics. Patients with preterm labor and advanced cervical dilation (greater than 4 cm), gestational age more than 36 weeks, or contraindication(s) to tocolysis were allowed to deliver. Otherwise, tocolysis was started, using fenoterol (2 µg/minute as a continuous infusion, adjusting the final dose according to response at 0.5 µg/minute intervals) or magnesium sulfate (starting with a 4-g bolus followed by 2 g/hour as a continuous infusion) (Figure 1
). Doppler velocimetry measurements in the uterine artery were performed at admission whenever possible. At delivery, the placenta was sent to the pathologist (who was blinded to the clinical course). Amniocentesis was performed when intra-uterine infection was suspected clinically (failure of tocolysis, maternal temperature greater than 37.8C, or a maternal white cell count greater than 14,000). A Gram stain, white cell count, and standard microbiologic cultures, including mycoplasma/ureaplasma, were performed on amniotic fluid (AF).
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of .05, and ratio, cases compared with control, 3:1) indicated that 120 patients in the study group and 40 control patients were needed. None of the study patients reported smoking or use of alcohol or street drugs in the 5 days before the onset of preterm labor. All patients (both preterm labor and control) were middle class with at least a high school education.
Patients presenting with multiple gestation, fetal death, major fetal malformations, fetal distress, pregnancy-induced hypertension, or other conditions that would significantly modify clinical management were not enrolled.
At delivery, all (study and control group) placentas were sent for histopathologic examination and the characteristics of all patients and newborns were recorded. Newborns admitted to the neonatal intensive care unit (NICU) were observed until discharge or demise. Diagnostic criteria to evaluate perinatal morbidity were those used in standard newborn care.
Uteroplacental Doppler measurements were performed as described previously,8 using a 3.5-MHz convex probe. Two investigators performed all the studies. Measurements were performed in the absence of uterine contractions. The uterine artery was assessed at the abdominal wall at the point where it crosses the iliac artery. At least five similar waves were obtained before measuring the systolic-diastolic (S/D) ratio. The intraobserver variation coefficient was 4.5%. The interobserver variation coefficient was 6.5%. In addition to the quantitative measurements of uterine artery resistance and to facilitate comparison with previously reported series, the cutoff value for normality was set at an S/D over 2.6 or by the presence of a diastolic notch.8
A single pathologist performed the gross and microscopic analysis of the placenta. Interpretation of findings was made according to standard criteria of the American College of Pathology.9 Placentas were then classified into groups according to the following criteria. For ischemic changes, decidual vasculopathy or placental infarction was present. For infectious changes, inflammation of the umbilical cord (including vessels), chorioamnionitis of placental or extraplacental membranes, and acute decidual inflammation were noted. Placentas without specific histopathologic findings were grouped as not classifiable to differentiate them from normal placentas. This group was composed of placentas that showed minimal focal subchorionic inflammation (n = 6), focal villous fibrosis (n = 4), focal villous accelerated maturation (n = 3), focal villous retarded maturation (n = 3), microcalcifications (n = 3), focal villous edema (n = 3), focal subchorionic fibrin deposits (n = 3), and miscellaneous (n = 7). Placental weight percentiles were calculated, and those placentas weighing less than the 10th percentile were classified as small.10
To integrate the observed clinical and pathologic changes, we also classified patients with preterm labor into four subgroups on the basis of maternal characteristics, uterine artery Doppler evaluation, and placental pathology. The groups were defined as follows: 1) no identifiable cause or idiopathic: patients with normal uterine artery Doppler, placental weight between 10th and 90th percentile, and normal or unclassifiable placental pathology; 2) ischemic: patients with at least two of the following: abnormal uterine artery Doppler (S/D greater than 2.6 or the presence of a notch in at least one of the uterine arteries), placental weight below the 10th percentile, or placental histopathologic examination indicating ischemia and absence of infection; 3) infectious: patients with acute placental inflammation or clinical chorioamnionitis and no criteria for ischemia; and 4) mixed: patients who met criteria for both ischemia and infection. Although some patients did not have uterine artery Doppler studies performed, all those who had the clinical and placental pathology information were included in the analysis.
Statistical analyses were made using 
2, one-way analysis of variance, and Student-Newman-Keuls for multiple comparisons. A difference was considered significant when the P value was equal to or lower than .05. In addition, the risk ratio and the 95% confidence interval (CI) were calculated. All statistical analyses were made using SAS software (Statistical Analysis System, Version 6.0, SAS Institute Inc., Cary, NC).
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Results |
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). The control group consisted of 44 patients. Patients in the study group had a higher gravidity and parity than the control group (mean ± standard error of the mean [SEM], 2.3 ± 0.1 and 1.0 ± 0.1 compared with 1.8 ± 0.2 and 0.6 ± 0.1, respectively; P < .001). Maternal age (28.5 ± 0.8 years compared with 29.1 ± 0.9 years) and the number of abortions (0.3 ± 0.07 compared with 0.3 ± 0.08) were similar.
The results of the histopathologic examination of placentas obtained from patients with preterm labor and in the control group were classified into five categories (Table 1). Compared with the control group, placentas from those in the study group who delivered preterm demonstrated a clear increase in the frequency of pathologic changes indicating ischemia or infection.
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). Of all patients who underwent uterine artery Doppler studies (66 patients in the study group and 42 in the control group), an abnormal uterine artery Doppler evaluation in patients presenting with preterm labor had a sensitivity of 62.9% and a specificity of 77.4%. The positive predictive value was 75.9% and the negative predictive value was 64.9% for the prediction of preterm delivery.
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). Of all patients with preterm labor, 28.3% were classified as ischemic, compared with 4.5% of the control group (odds ratio [OR] and 95% CI = 8.28 [1.8, 51.8]; P < .05). For those patients who actually delivered preterm, 31.4% were classified as ischemic, which differs significantly from both controls and those with preterm labor that delivered at term. The preterm delivery group also had a higher rate of ischemia and infection than the control group (Table 3).
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). No significant differences were observed among the different subgroups in failure of tocolysis (delivery before 48 hours), premature preterm rupture of membranes, pregnancy-induced hypertension, antepartum hemorrhage, or cesarean delivery (data not shown).
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. The ischemic subgroup demonstrated a higher rate of admission to NICU (OR [95% CI] = 2.32 [1.01, 5.38]; P < .05), newborn weight less than 1500 g (OR [95% CI] = 6.38 [1.41, 32.7]; P < .05), and weight under the 10th percentile for our population (OR [95% CI] = 2.98 [1.06, 8.49]; P < .05) than the idiopathic subgroup. Compared with the idiopathic subgroup, the infectious subgroup demonstrated a higher rate of admission to the NICU (OR [95% CI] = 4.45 [1.34, 15.68]; P < .05), more newborn weights less than 1500 g (OR [95% CI] = 14.18 [2.78, 81.25]; P < .05), and a higher perinatal mortality (P < .05).
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Discussion |
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Some authors have reported a correlation between placental findings of ischemia in patients delivering preterm,7 whereas others have reported the association of abnormal Doppler studies and prematurity.8,11,12 In the present study, we report in the same population the clinical, functional (Doppler), and morphologic (placental pathology) evidence of ischemia to attempt to better understand its role as a cause of preterm delivery. The infectious etiology of preterm labor has been investigated more intensively because it is possible to study the presence of infectious organisms in the AF, cervix, and vagina. The ability to explore the mediators involved in triggering preterm labor in the setting of intrauterine infection has produced enormous advances in understanding the circumstances leading to preterm labor in about 13% of patients. The percentage of preterm labor with an infectious etiology in this study is similar to that reported in the literature and previously from our own center.3,4 Of note, the liberal use of amniocentesis did not increase significantly the percentage of preterm deliveries associated with infection.
In the present study, placental ischemic changes correlated with functional changes reflected by an abnormal uterine artery Doppler value. These findings are again similar to those described by others.2,8,11 Other studies, however, did not correlate clinical findings with placental pathology or neonatal outcomes. In our population of patients with preterm labor, S/D values coupled with the presence of a notch in at least one uterine artery demonstrated only moderate performance as a predictor of preterm delivery, probably reflecting the fact that ischemia is the origin of preterm labor in only a subset of patients. In addition, the present data are compatible with the reported correlation between uterine artery Doppler values and the extent of trophoblast migration in the myometrium in patients delivered at term and preterm.13 If the uterine artery S/D was higher than 2.5 (a cutoff point similar to that used in our series), 92% of cases demonstrated impaired trophoblast migration and abnormal physiologic changes in the spiral arteries.
Interestingly, the placental and uteroplacental lesions observed in the setting of preterm birth are similar to those described in preeclampsia.7,14–16 Moreover, histopathologic studies performed in placentas obtained from patients with non-preeclamptic prematurity indicate that increasing severity of uteroplacental vascular and related villous lesions is associated with higher blood pressure on admission.17 This suggests that worsening placental ischemia can manifest as either preeclampsia or preterm labor. We can speculate that similar placental vascular damage may account for very different clinical manifestations, depending on myometrial quiescence status, genetic susceptibility, vascular reactivity, or unknown factors. Moreover, it is possible to hypothesize that the underlying defect in patients with preterm labor of ischemic origin is faulty placentation leading to ischemia, as has been proposed recently for preeclampsia.18
Compared with the idiopathic group, women presenting with uteroplacental ischemia had poorer perinatal outcomes. This highlights the potential prognostic implications of differentiating between the causes of preterm labor. The statistical power study of our data indicates that with a power of 80%, and significance set at P < .05, about 130 patients in each category of preterm labor would be needed to demonstrate differences in perinatal outcome compared with idiopathic preterm labor. Nevertheless, combining major neonatal morbidity and perinatal mortality as a whole suggests that preterm labor of ischemic and infectious origins has a poorer prognosis than idiopathic preterm labor.
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Footnotes |
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Received June 29, 1998. Received in revised form January 27, 1999. Accepted February 3, 1999.
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References |
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2. Romero R, Mazor M, Muñoz H, Gomez R, Galasso M, Sherer D. The preterm labor syndrome. Ann N Y Acad Sci 1994;734:414–29.[Medline]
3. Gomez R, Romero R, Edwin S, David C. Pathogenesis of preterm labor and premature rupture of membranes associated with intra-amniotic infection. Infect Dis Clin North Am 1997;11:135–76.[Medline]
4. Oyarzun E, Gomez R, Rioseco A, Gonzalez P, Gutierrez P, Donoso E, et al. Antibiotic treatment in preterm labor and intact membranes. A randomized double blind placebo controlled trial. J Matern Fetal Med 1998;7:105–10.[Medline]
5. Romero M, Sirtori, Oyarzún E, Avila S, Mazor M, Callahan R, et al. Infection and labor V. Prevalence, microbiology and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989;161:817–24.[Medline]
6. Arias F, Rodriguez L, Rayne SC, Krauss FT. Maternal placental vasculopathy and infection: Two distinct subgroups among patients with preterm labor and preterm ruptures membranes. Am J Obstet Gynecol 1992;168:586–91.
7. Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J, Silberman L. Placental pathologic findings in preterm birth. Am J Obstet Gynecol 1991;165:934–8.[Medline]
8. Brar HS, Medearis AL, DeVore GR, Platt LD. Maternal and fetal blood flow velocity waveforms in patients with preterm labor: Prediction of successful tocolysis. Am J Obstet Gynecol 1988;159: 947–50.[Medline]
9. Langston C, Kaplan C, Macpherson T, Manci E, Peevy K, Clark B, et al. Practice guideline for examination of the placenta. Arch Pathol Lab Med 1997;121:449–76.[Medline]
10. Naeye RL. Disorders of the placenta and decidua. In: Naeye RL, ed. Disorders of the placenta, fetus and neonate: Diagnosis and clinical significance. 1st ed. St. Louis, MO: Mosby Year Book Inc, 1992:118–247.
11. Rizzo G, Capponi A, Arduini D, Turri E, Romani C. Uterine and fetal blood flows in pregnancies complicated by preterm labor. Gynecol Obstet Invest 1996;42:163–6.[Medline]
12. Strigini FAL, Lencioni G, DeLuca G, Lombardo M, Bianchi F, Genazzani AR. Uterine artery velocimetry and spontaneous pre-term delivery. Obstet Gynecol 1995;85:374–7.[Abstract]
13. Lin S, Shimizu Y, Suehara N, Nakayama M, Aono T. Uterine artery Doppler velocimetry in relation to trophoblast migration into the myometrium of the placental bed. Obstet Gynecol 1995;85:760–5.[Abstract]
14. Redman CWG. Current topic: Preeclampsia and the placenta. Placenta 1991;12:301–8.[Medline]
15. Salafia CM, Vogel CA, Bantham KF, Vintzileos AM, Pezzullo J, Silberman L. Preterm delivery: Correlation of fetal growth and placental pathology. Am J Perinatol 1992;9:190–3.[Medline]
16. Salafia CM, Pezzullo JC, Lopez-Zeno JA, Simmens S, Minior VK, Vintzileos AM. Placental pathology of preterm preeclampsia. Am J Obstet Gynecol 1995;173:1097–105.[Medline]
17. Salafia CM, Ghidinni A, Lopez-Zeno JA, Pezullo JC. Uteroplacental pathology and maternal arterial mean blood pressure in spontaneous prematurity. J Soc Gynecol Invest 1998;5:49–57.[Medline]
18. Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun SH, et al. Human cytotrophoblast differentiation/invasion is abnormal in preeclampsia. Am J Pathol 1997;151:1809–18.[Abstract]
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